DESCRIPTION: Deficient insulin secretion by ? cells of the islets of Langerhans is critical to the development of type 2 diabetes (T2D). We propose that autoimmune processes directed against islet cells comprise a significant mechanism leading to ? cell dysfunction in patients wit T2D. Emerging data from our collaborative group indicate that a substantial proportion of patients with T2D have multiple manifestations of islet autoimmunity - including islet-reactive T cells, islet autoantibodies and absence of anti-idiotypic antibodies - associated with accelerated beta cell dysfunction. Identification of different forms of islet autoimmunity is crucial to understanding the causes and natural history of ? cell dysfunction in T2D, as well as for targeted treatment approaches. We hypothesize, based on careful natural history studies and evidence for systemic and islet inflammation in T2D patients, that early and ongoing islet injury is a cardinal feature of T2D. In susceptible patients, this leads to breakdown of immune tolerance, followed by the development of islet-specific T cell reactivity and autoantibodies with disease-specific epitope patterns. The GRADE Trial, with its schedule of annually repeated oral glucose tolerance tests with insulin measurements, provides a matchless opportunity to investigate these immune-mediated mechanisms of ? cell function loss in longitudinally-tracked T2D patients, as well as the impact on these mechanisms of antidiabetic drugs with different modes of action. To test this hypothesis, we will achieve the following Specific Aims: 1. Determine, in T2D patients enrolled in the GRADE Trial, the relationship between T cell reactivity to islet autoantigens and loss of ? cell function over time and in response to treatmen; 2. Determine, in the same patients as in Aim 1, the relationship between islet autoantibodies, their epitopes, anti-idiotypic antibodies and loss of ? cell function over time and in response to treatment; 3. Discover and confirm, in the same patients as in Aim 1, serum proteins related to islet cell injury, and determine their relationship to loss of ? cell function over time and in response to treatment; 4: Discover a network of interactions among the markers measured in Aims 1-3, as well as their association with loss of ? cell function. The significant questions thi project hopes to answer are: 1) How prevalent is islet autoimmunity - in all its manifestations - among patients with T2D? 2) Does islet autoimmunity portend a faster rate of ? cell function decline in T2D? 3) Can any GRADE interventions attenuate the autoimmunity-associated rate of ? cell function decline? To answer these questions, our collaborative research group will utilize state-of-the-art methods to measure islet injury marker proteins, anti-idiotypic antibodies, epitope-specific islet autoantibodies, and islet- specific T cell reactivity to delineate pathways f ? cell dysfunction, track ? cell function longitudinally in the large, heterogeneous GRADE T2D population, and employ innovative statistical modeling methods to analyze and integrate the data and discover a network of interactions among these biomarkers.